Staphylococcus aureus, a commensal of the human skin and nares, is also an invasive pathogen and frequent cause of skin and soft tissue infections, bacteremia and sepsis. Many clinical isolates are resistant against commonly used antibiotics and these strains are collectively referred to as methicillin-resistant S. aureus (MRSA). The annual survival rate of patients with MRSA sepsis is less than 50%. S. aureus is the only bacterial pathogen known to coagulate plasma and to agglutinate with fibrin cables in blood. We show here that this agglutination phenotype is based on the secreted products from three genes (coa, vwb, clfA) as well as several non-secreted gene products. We propose a new model whereby S. aureus agglutination involves the formation of staphylothrombin (Coa, vWbp)-assembled fibrin cables, which are capped by clumping factor A (ClfA) on the staphylococcal surface and crosslinked by factor XIII. We hypothesize further that S. aureus agglutination provides for escape from phagocytic killing and promotes the formation of discrete abscess lesions, where staphylococci replicate as a bacterial community, protected from immune cells. This key virulence strategy may be perturbed with monoclonal antibodies and small molecule inhibitors to either prevent or treat S. aureus sepsis. Preliminary work demonstrated that S. aureus Coa and vWbp each associate with host prothrombin to form multi-protein complexes in human plasma (with prothrombin, fibrinogen, fibronectin and factor XIII) dedicated to the formation of cross-linked fibrin cables. Staphylococcal agglutination involves the surface display of functional ClfA, which requires several gene products [aggABCD, (staphylococcal agglutination genes)] that appear to modify ClfA prior to sortase A-mediated anchoring in the bacterial cell wall envelope (srtA). In addition to genetic loss-of-function analysis, we will also reconstitute agglutination in vitro from purified components and in vivo by expressing genes in Staphylococcus epidermidis, an opportunistic pathogen that cannot agglutinate or form discrete abscess lesions. Monoclonal antibodies (mAbs) -isolated against purified Coa, vWbp or ClfA- and small molecule inhibitors are being used to perturb staphylococcal agglutination in vitro and in vivo and examined for the provision of protection or therapy in a mouse model of S. aureus sepsis.